Project Summary An ideal influenza vaccine must have two essential attributes: one, it should be capable of inducing broadly cross-reactive antibodies that can neutralize diverse influenza virus strains; and two, it must induce long-lived antibody responses to maintain protective immunity for extended periods. The licensed inactivated influenza virus vaccine does neither ? the antibody response is of limited breadth and vaccine-induced immunity appears to be of short duration. Our preliminary results show that the currently used seasonal inactivated trivalent influenza vaccine (TIV) is not efficient in generating long-lived bone marrow plasma cells in humans and that this is the cellular defect that underlies the waning immunity seen after influenza vaccination. In addition, our recent data suggest that there is minimal somatic hypermutation in influenza-specific B cells after immunization with TIV. This suggests that the vaccine fails to elicit the robust germinal center responses that are thought to be required for generating long-lived plasma cells. As we move towards the goal of developing a ?Universal? influenza vaccine, there is a compelling need for a product that will provide long-lasting protection against many different strains of influenza viruses. Previous studies have shown that some live attenuated viral vaccines or infections are able to induce antibody responses that persist for a lifetime in humans, while responses to protein vaccines typically decline much faster. This suggests that there are qualitative differences in the plasma cells elicited by live versus inactivated vaccines. Our proposal addresses fundamental questions about the generation of influenza-specific long-lived plasma cells and their persistence in the bone marrow both in humans and in mice following vaccination or infection. The following specific aims are proposed: Specific Aim 1; To determine the duration of humoral immunity to influenza virus infection versus vaccination in humans; and Specific Aim 2: To optimize strategies for using adjuvants and the vaccine candidates developed in this program project to generate long lived bone marrow plasma cells in mice. Our studies will be highly synergistic with other projects and cores in this Program Project grant.